synthon polymorphs of sulfacetamide−acetamide cocrystal ... · university po, hyderabad 500 046,...

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Synthon polymorphs of sulfacetamide−acetamide cocrystal based on

N−H···O=S and N−H···O=C hydrogen bonding†

N. Rajesh Goud, and Ashwini Nangia*

School of Chemistry, University of Hyderabad, Prof. C.R. Rao Road, Gachibowli, Central

University PO, Hyderabad 500 046, India. E-mail: [email protected]

Electronic Supplementary Information†

Table S1 List of polymorphic molecules with the SO2-NH-CO fragment in Organic crystal

structures retrieved from the Cambridge Structural Database (CSD, ver. 5.34, Conquest 1.15,

November 2012 release).

Chlorpropamide, BEDMIG

5 polymorphs

Glimepiride, TOHBUN

2 polymorphs

Torasemide, TORSEM

3 polymorphs

Carbamazepine-Saccharin, UNEZAO

2 polymorphs

Electronic Supplementary Material (ESI) for CrystEngCommThis journal is © The Royal Society of Chemistry 2013

S2

Ethenzamide-Saccharin, VUHFIO

2 polymorphs

Tolbutamide, ZZZPUS

6 polymorphs

Table S2 Hydrogen bond synthon patterns (rings, chains, etc.) in polymorphic compounds with

the SO2NHCO functional group (listed in Table S1).

Chlorpropamide – 5 polymorphs

P21

Urea tape-motif, with one of the hydrogen atom

in the tape bifurcating to form N–H···O=S H-

bond

Pbcn

Catemeric N–H···O=C H-bond


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Pbca

Two point synthon comprised of N–H···O=C

and N–H···O=S H-bonds

Pna21

Synthon similar to P21 structure

P212121

Synthon similar to P21 structure

Glimepiride – 2 polymorphs


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Pbca

Urea-tape motif

P21/n

Carboxamide dimer

Torasemide – 3 polymorphs

P21/c

Carboxamide dimer and catemer

P2/n

N–H···O=S dimer ring motif


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P21/c

Zwitterionic polymorph N–H···O=S dimer type

along with bifurcated N–H···C=O and N–

H···S=O H-bonds

Tolbutamide – 3 polymorphs

P21/n

Cyclic synthon of N–H···O=C and N–H···O=S

H-bonds

P21/c

Cyclic motif of N–H···O=C and N–H···O=S

H-bonds


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Pbcn

Cyclic synthon of N–H···O=C and N–H···O=S

H-bonds

Ethenzamide−saccharin cocrystal – 2 polymorphs

P-1

Catemer N–H···O=C and N–H···O=S H-bonds

P21/c

Carboxamide dimer synthon


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Carbamazepine−saccharin cocrystal

P-1

Carboxamide homodimer along with N–

H···O=S H-bond with saccharin

P21/c

N–H···O=S and N–H···O=C heterodimer

Table S3 CSD Refcodes of neutral polymorphic cocrystals retrieved from the last full release of

the CSD, ver. 5.34, Conquest 1.15, November 2012 release).

Entry Cocrystal Polymorph REFCODEs

1

ABEKUN

ABEKUN01

ABEKUN02

2

ABUNIU

ABUNIU01

3

ACOYOG

ACOYOG01


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4

AJAJEA

AJAJEA01

5

ANTCYB,

ANTCYB12

ANTCYB11

ANTCYB13

ANTCYB14

ANTCYB15

ANTCYB16

6

ANUMEC

ANUMEC01

7

BIVSIJ01

BIVSIJ02

8

CAZLAR,

CAZLAR01

CAZLAR02

9

COHWIF,

COHWIF02,

COHWIF03

COHWIF01

10

DOKGUG

DOKGUG01


S9

11

DURZAR

DURZAR01

12

EFOZAB,

EFOZAB03

EFOZAB01

EFOZAB04

EFOZAB02

13

ELEGUY

ELEGUY01

14

ENAZOI

ENAZOI01

15

EPUPUB

EPUPUB01

16

EXUQUJ

EXUQUJ01

17

FAHLEF01

FAHLEF02


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18

FIHYEA

FIHYEA02

19

HADKUT

HADKUT01

20

IJETOG

IJETOG02

21

IJIBEJ

IJIBEJ01

22

KIBQOC

KIBQOC01

23

KIHYOQ

KIHYOQ01

24

LOCVOO

LOCVOO01


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25

LOFKIB

LOFKIB01

26

MIYKOU

MIYKOU01

27

MOXVIF

MOXVIF01

28

MUROXA

MUROXA01

29

NAPYMA

NAPYMA01

30

NARSOP

NARSOP01

NARSOP02

31

NITRIR

NITRIR01


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32

NOVSIA

NOVSIA01

33

NUGZEV

NUGZEV01

34

NUKWEW

NUKWEW01

35

NUKXEX

NUKXEX01

36

ODOBIT

ODOBIT01

37

PTZTCQ

PTZTCQ01

38

QUIDON

QUIDON01

QUIDON02


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39

QULLUF

QULLUF01

QULLUF02

40

RIFQAY

RIFQAY01

41

RIWWEA

RIWWEA01

42

RURROM

RURROM01

43

SAYMUB

SAYMUB01

44

TAMBUE

TAMBUE01

45

TECCAF01

TECCAF02


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46

TEHNAW

TEHNAW01

47

TIPWIY

TIPWIY01

48

TONDUV

TONDUV02

49

TUPRBN01

TUPRBN10

50

ULAWAF

ULAWAF01

ULAWAF02

51

UNEZAO

UNEZAO01

52

VAKTOS

VAKTOS01


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53

VEJXAJ

VEJXAJ01

54

VUHFIO

VUHFIO01

55

VUJSOJ

VUJSOJ01

56

WANNUV

WANNUV01

57

WATREP,

WATREP01

WATREP04

WATREP02

WATREP03

58

WOBQEK

WOBQEK01

59

WOTZAG

WOTZAG01


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60

WUZHOP

WUZHOP01

61

XETZIG

XETZIG01

62

XOLHUC

XOLHUC01

XOLHUC02

63

YABHAM

YABHAM01

64

ZODWIY

ZODWIY01

65

ZZZGMW01

ZZZGMW02

66

EWAPAU

EWAPAU01


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67

EXAPID

EXAPID01

68

UBUJIM

UBUJIM01

69

PANQUS

PANQUS01

70

AWIHOE02

AWIHOE03

AWIHOE04

AWIHOE05

AWIHOE06

AWIHOE07

AWIHOE08

AWIHOE09

AWIHOE10

71

YASGOQ

YASGOQ01

YASGOQ02

YASGOQ03

72

N

N

CH3

HOOC

COOH

WOQBAF

WOQBAF01


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Fig. S1 Overlay of SACT and ACT molecules in cocrystal form 1 (blue) and 2 (magenta).


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Fig. S2 Comparison of PXRD patterns of the samples obtained in the grinding experiments of

1:1 mixture of SACT and ACT. Solvent used in grinding experiments is indicated on the right.

The resulting powder pattern did not follow any trend based on the polarity of solvent used.


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Table S4 ss-NMR 13

C chemical shifts (, ppm) of SACT−ACT cocrystal polymorphs.

Carbon No. SACT-ACT-FORM-1 SACT-ACT-FORM-2

8 20.8 20.3

10 24.4 25.4

2,6 112.9 111.4, 113.2

4 123.1 120.2

5 129.3 127.5

3 134.3 132.7

1 154.6 154.5

9 172.8 173.5

7 175.3 175.8

(a)

(b)

Fig. S3 IR and Raman spectra of SACT-ACT cocrystal polymorphs.


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Fig. S4 Heat-cool-heat DSC heating curve of SACT-ACT Form 2 indicated that the high

temperature phase is form 1.

Eqn. S1 Calculation of melting point of SACT−ACT metastable form 2 (taken from ref. 15).

ΔHfus (form 2) = Enthalpy of fusion of form 2 (Enthalpy of fusion of form 1 + Enthalpy of

Transition) = 32.3 kJ/mol

Tfus (form 1) = Temperature of fusion of form 1 = 106.5°C

Ttrs = Temperature of transition from form 2 to form 1 = 79°C


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ΔHfus (form 1) = Enthalpy of fusion of form 1 = 29.5 kJ/mol

Tfus (form 2) = Temperature of fusion of form 2 (calculated) = 103.4°C

Form 1

Form 2

Fig. S5 HSM snapshots of SACT−ACT cocrystal polymorphs. Significant morphological

changes were observed between 81-83 °C in form 2 whereas form 1 exhibited clean melting

behavior.


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Fig. S6 Semi-quantitative E/T curves to show the stability of SACT−ACT polymorphs. Form 2

is the thermodynamic polymorph at absolute zero (−273 °C) and up to RT. Form 2 undergoes a

phase transition at 83 °C to form 1. Form 1 is stable from 83 °C up to the melting temperature of

107 °C. Form 2 is stable between 25-83 °C, which is in agreement with the slurry and grinding

experiments of form 1 converting to form 2, and form 2 being stable to these conditions. The

dashed line indicates that the polymorph has transformed to another form at that temperature,

Ttrs.


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(a)

(b)

(c)

Fig. S7 (a) Experimental PXRD of SACT−ACT form 1 after neat grinding in ball mill for 30

min matches with that of form 2. There is no change for form 2. (b) Experimental PXRD of a 1:1

mixture of SACT−ACT form 1 and 2 converted to form 2 after neat grinding in ball mill for 10

min. (c) Experimental PXRD of SACT−ACT form 2 did not show any change after neat grinding

in ball mill for 3 h.


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Fig. S8 Melt cooling of SACT–ACT form 1 or form 2 resulted in the crystallization of form 1 in

either case, consistent with the Ostwald’s Law of Stages. Thus melt cooling establishes form 1 as

the kinetic, metastable modification.


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0 50 100 150 200 250

0

100

200

300

400

500

600

700

800

900

1000

Cu

mu

lati

ve

am

ou

nt

dis

solv

ed i

n m

g/c

m2

Time in mins

SACT

SACT-ACT-FORM-1

SACT-ACT-FORM-2

Fig. S9 IDR curves of SACT–ACT polymorphs in pH7 buffer medium.

Table S5 Intrinsic dissolution rates of SACT polymorphs along with their molar extinction

coefficient (), and AUC values. The number of times enhancement of IDR and AUC with

respect to SACT is given in parentheses.

Compound Molar Extinction

coefficient (/mM/cm) Equi. Sol.

(g/L) IDR

(mg/cm2/min)

AUC0-4h

(mg h/L)

SACT 22.8 14.5 2.18 64,763

SACT–

ACT

form 1

17.9 -- 3.4 (x 1.57) 105,679 (x1.63)

SACT–

ACT

form 2

19.9 -- 2.8 (x 1.27) 80,853 (x1.25)


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(a)

(b)


S28

(c)

Fig. S10 Stability measurement at the end of the solubility experiment (24 h) in the slurry

medium. (a) PXRD of SACT at the end of the equilibrium solubility experiment matches with

the calculated XRD lines of the crystal structure, indicating form stability. (b) PXRD of

SACT−ACT form 1 at the end of the equilibrium solubility experiment matches with the

calculated XRD lines of SACT, indicating dissociation of the cocrystal. (c) PXRD of

SACT−ACT form 2 at the end of the equilibrium solubility experiment (24 h) matches with the

calculated XRD lines of SACT, indicating dissociation of the cocrystal


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(a)

(b)

Fig. S11 PXRD plots of SACT and its cocrystal polymorphs at the end of the dissolution

experiment (4 h). (a) PXRD of SACT−ACT form 1 at the end of the dissolution experiment (4 h)

matches with the calculated XRD lines of SACT, indicating dissociation of the cocrystal. (b)

PXRD of SACT−ACT form 2 at the end of dissolution experiment (4 h) matches with the

calculated XRD lines of SACT, indicating dissociation of the cocrystal.


S30

Experimental Section

Phase transformation experiments

Grinding experiments were done on 100 mg scale. Competitive grinding experiments were

carried out on 1:1 stoichiometric ratio of the polymorphs (100 mg each). A Retsch mixer-mill

equipped with a 5 mL stainless steel grinding jar and SS balls of 4 mm diameter was used for

mechanical grinding. Slurry experiments were also done on 100 mg scale. Competitive slurry

experiments were carried out on 1:1 stoichiometric ratio of the polymorphs (100 mg each).

Toluene (5 mL in each experiment) was used as solvent in slurry experiments.

Single crystal X-ray diffraction

Crystal structures of the polymorphs were collected on CrysAlisPro, Oxford Diffraction Ltd.,

Version 1.171.33.55 with SCALE3 ABSPACK absorption correction, Xcalibur, EOS, Gemini

measurement device and Mo-Kα (λ = 0.71073 Å) radiation.1 Data reduction and structure

refinement was performed using OLEX2 software.2 Non-hydrogen atoms were refined

anisotropically. C–H hydrogen atoms were positioned geometrically and refined in the riding

model approximation. The methyl group in the ACT molecule has relatively large ADPs due to

libration of H atoms. Attempts to split the electron density over two locations gave negative s.o.f.

for the second C position, and so the process was abandoned. A check of the final CIF file using

PLATON3 did not show any missed symmetry. Hydrogen bond distances shown in Table 2 are

neutron normalized to fix the D–H distance to its accurate neutron value in the X-ray crystal

structures (O–H 0.983 Å, N–H 1.009 Å, and C–H 1.083 Å). After the final refinement, structure

analysis and preparation of art works were carried out using MERCURY and X-SEED

4 software.

Vibrational spectroscopy

Thermo-Nicolet 6700 Fourier transform infrared spectrophotometer with NXR-Fourier transform

Raman module (Thermo Scientific, Waltham, Massachusetts) was used to record IR and Raman

spectra. IR was recorded on samples dispersed in KBr pellets. Raman spectra were recorded on

samples contained in standard NMR diameter tubes or on compressed samples contained in a

gold-coated sample holder. Data were analyzed using the Omnic software (Thermo Scientific,

Waltham, Massachusetts).

Thermal analysis

Differential scanning calorimetry was performed on a Mettler-Toledo DSC 822e module

(Mettler-Toledo, Columbus, Ohio). Samples were placed in crimped but vented aluminum pans

for these experiments. The typical sample size is 3−5mg for the experiment. The temperature

range for the heating curve was 30−150 °C and the sample was heated at a rate of 10°C/min.

Samples were purged in a stream of dry nitrogen flowing at 80 mL/ min. Melting point of SACT-

ACT form 2 was determined by heating the sample from 30−150 °C at a heating rate of 125

°C/min.

Powder X-ray diffraction


S31

Powder X-ray diffraction of the polymorphs were recorded on Bruker D8 Focus diffractometer

(Bruker-AXS, Karlsruhe, Germany) using Cu-Kα X-radiation (λ = 1.5406 Å) at 40 kV and 30

mA power. X-ray diffraction patterns were collected over the 2θ range 5–50° at a scan rate of 1º

/min. Powder Cell 2.4 (Federal Institute of Materials Research and Testing, Berlin, Germany)

5

was used for Rietveld refinement of experimental PXRD and calculated lines from the X-ray

crystal structure. VT-PXRD was performed on the same instrument equipped with a variable

temperature stage -TTK450 module. PXRD patterns for both the forms were collected at 30, 60,

80, 86 and 92 ºC. All the powder patterns were plotted using Origin 7.0 software.

Hot stage microscopy

HSM was performed on a Wagner & Munz PolythermA Hot Stage and Heiztisch microscope. A

Moticam 1000 (1.3 MP) camera supported by software Motic Image Plus 2.0ML is used to

record images.

Solid-state NMR spectroscopy

Solid-state 13

C NMR spectra were recorded on Bruker Avance 400 MHz spectrometer (Bruker-

Biospin, Karlsruhe, Germany). SS-NMR measurements were carried out on Bruker 4-mm double

resonance CP-MAS probe in zirconia rotors with a Kel-F cap at 5.0-kHz spinning rate with a

cross-polarization contact time of 2.5 ms and a delay of 8 s. 13

C NMR spectra were recorded at

100 MHz and referenced to the methylene carbon of glycine, and then recalibrated to the TMS

scale (δglycine = 43.3 ppm).

Cambridge Structural Database

The CSD (version 5.34, ConQuest 1.15, November 2012 release)6 was searched for cocrystal

polymorphs. The parameters “all polymorphic structures with 3D coordinates determined”, “no

errors”, “no polymeric”, and “no ions” were searched to give 6539 hits. Crystal structures were

visualized with Mercury 2.0, and 72 sets of cocrystal polymorphs were manually retrieved (3D

coordinates reported for all polymorph sets). Crystal structures with any degree of disorder were

excluded. Details of polymorphic cocrystal sets are listed in the Supporting Information, Table

S3.

Dissolution and Solubility measurements

The solubility curves of cocrystal polymorphs were measured using the Higuchi and Connor

method7 in pH 7 buffer medium at 30 °C. First, the absorbance of a known concentration of the

polymorphs was measured at the given λmax (SACT at 256 nm and SACT-ACT form 1 and 2 at

257 nm) in pH 7 buffer medium on Thermo Scientific Evolution 300 UV–vis spectrometer

(Thermo Scientific, Waltham, MA). These absorbance values were plotted against several known

concentrations to prepare the concentration vs. intensity calibration curve. From the slope of the

calibration curves, molar extinction coefficients for the polymorphs were calculated. An excess

amount of the sample was added to 6 mL of pH 7 buffer medium. The supersaturated solution

was stirred at 300 rpm using a magnetic stirrer at 30 °C. After 24 h, the suspension was filtered

through 0.45μ syringe filter. The filtered aliquots were diluted sufficiently, and the absorbance

was measured at the given λmax. IDR experiments were carried out on USP-certified Electrolab


S32

TDT-08L dissolution tester (Mumbai, India). Dissolution experiments were performed for 4 hrs

in pH 7 buffer medium at 37 °C. Prior to IDR estimation, standard curves for all the compounds

were obtained spectrophotometrically at their respective λmax. The calculated molar extinction

coefficients were used to determine the IDR values. For IDR measurements, 500 mg of the

compound was taken in the intrinsic attachment and compressed to 0.5-cm2 disk using a

hydraulic press 2.5 ton/in2 pressure for 4 min. The intrinsic attachment was placed in a jar of 900

mL medium preheated to 37 °C and rotated at 150 rpm. 5 mL of the aliquot was collected at

specific time intervals, and the concentration of the aliquots was determined with appropriate

dilutions from the predetermined standard curves of the respective compounds. The IDR of the

compound was calculated in the linear region of the dissolution curve (which is the slope of the

curve or amount of drug dissolved/surface area of the disk) per unit time. The identity of the

undissolved material after the dissolution experiment was ascertained by PXRD. The nature of

the solid samples after disk compression and solubility/dissolution measurements were verified

by PXRD.

References

1. CrysAlis CCD and CrysAlis RED, Versions 1.171.33.55, Oxford Diffraction, Oxford,

2008.

2. O. V. Dolomanov, L. J. Bourhis, R. J. Gildea, J. A. K. Howard and H. Puschmann, J.

Appl. Crystallogr., 2009, 42, 339.

3. (a) A. L. Spek, PLATON: A Multipurpose Crystallographic Tool; Utrecht University:

Utrecht, The Netherlands, 2002. (b) A. L. Spek, J. Appl Crystallogr., 2003, 7, 36.

4. (a) L. J. Barbour, Supramol. Chem. 2001, 1, 189; (b) L. J. Barbour, X-Seed, Graphical

Interface to SHELX-97 and POV-Ray; University of Missouri-Columbia: Columbus,

MO, 1999.

5. Powder Cell, a program for structure visualization, powder pattern calculation and profile

fitting. http://www.ccp14.ac.uk/tutorial/powdcell/.

6. Cambridge Structural Database, CSD, version 5.34, ConQuest 1.15, Nov 2013 update.

7. T. Higuchi and K. A. Connors, Adv. Anal. Chem. Instrum., 1965, 4, 117.


http://www.ccp14.ac.uk/tutorial/powdcell/

synthon polymorphs of sulfacetamide−acetamide cocrystal ... · university po, hyderabad 500 046,...

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